ABSTRACT Multiple myeloma (MM) claims over 80,000 lives globally each year. Although several new therapies have been approved over the past decade, virtually all patients relapse and the median survival remains at only 5 years. The depth of therapeutic response correlates with time to relapse, and eradicating tumor cells early in the disease process may be necessary to achieve clinical cure. A potentially curative approach is autologous cell therapy with chimeric antigen receptor (CAR) T-cells redirected to a target antigen. For MM, an attractive target antigen is B cell maturation antigen (BCMA), an antigen marker with extremely high sensitivity and specificity for myeloma and plasma cells. Experiments proposed in this SBIR will define a transiently- expressed anti-BCMA CAR product that will overcome the toxicities generated by permanently modified T- cells. The goals of the Specific Aims are to 1) reduce immunogenicity of transiently-expressed (mRNA) anti- BCMA CAR T-cells to target MM in vitro; 2) optimize T-cell activation domains for the RNA-based CAR construct; 3) optimize translation and degradation of the mRNA transcript in T cells, and 4) demonstrate anti- BCMA CAR T-cell function in two in vivo models of MM. Such transient expression allows for predictable and controllable treatment of myeloma and may enable CAR T-cell therapy to be used in patients with early disease, with vastly improved potential of achieving clinical cure.